Adverse Neurodevelopmental Outcomes Among Extremely Low Birth Weight Infants With a Normal Head Ultrasound: Prevalence and Antecedents
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《小儿科》
Brown Medical School, Providence, Rhode Island
Wake Forest University School of Medicine, Winston-Salem, North Carolina
Wayne State School of Medicine, Detroit, Michigan
Research Triangle Institute, Washington, DC
ABSTRACT
Objective. Severe abnormalities of the head ultrasound (HUS) are important predictors of cerebral palsy (CP) and mental retardation, and a normal HUS usually ensures the absence of major impairments. With the increasing survival of extremely low birth weight (ELBW) infants (birth weight <1000 g), the prognostic significance of a normal HUS may differ. This study examined the prevalence of and risk factors for CP and impaired mental development among ELBW infants with a normal HUS.
Methods. Study infants were ELBW infants who were cared for in Neonatal Research Network centers in the years 1995–1999, had a normal early and late HUS, survived to discharge, and returned for follow-up assessments at 18 to 22 months' corrected age. The outcomes of interest were a score <70 on the Bayley Scales of Infant Development-II Mental Developmental Index (MDI) and CP. Risk factors included maternal demographics; infant characteristics; and interventions or morbidities related to the lung, infection, and nutrition. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A time-oriented approach was used to select variables for inclusion in logistic models.
Results. Of 1749 infants with a normal early and late HUS (performed at a mean age of 6 and 47 days, respectively), 1473 (84%) returned for follow-up assessment. Infants had a birth weight of 792 ± 134 g (mean ± SD) and gestational age of 26 ± 2 weeks. Rates of CP and MDI <70 were 9.4% and 25.3%, respectively, and 29.2% of infants had either CP or MDI <70. In multivariate analyses, factors associated with CP were male gender (OR: 1.8; 95% CI: 1.2–2.6), multiple birth, (OR: 1.6; 95% CI: 1.1–2.5), decreasing birth weight (OR: 1.3 for each 100-g decrease; 95% CI: 1.1–1.5), pneumothorax (OR: 2.3; 95% CI: 1.2–4.4), and days of conventional ventilation (OR: 1.2 for each additional 10 days; 95% CI: 1.1–1.3). With the exception of pneumothorax, these same factors were associated with MDI <70, in addition to less maternal education (OR: 1.4; 95% CI: 1.0–1.9) and Medicaid or lack of coverage for maternal insurance (OR: 1.7; 95% CI: 1.2–2.4).
Conclusions. Nearly 30% of ELBW infants with a normal HUS had either CP or a low MDI. Risk factors that are associated with this high rate of adverse outcomes include pneumothorax, prolonged exposure to mechanical ventilation, and educational and economic disadvantage. Improvements in pulmonary care to reduce duration of ventilation and avoid air leaks might improve neurodevelopmental outcome for ELBW infants.
Key Words: brain imaging extremely preterm infants intraventricular hemorrhage neurobehavioral development
Abbreviations: ELBW, extremely low birth weight CP, cerebral palsy CLD, chronic lung disease HUS, head ultrasound IVH, intraventricular hemorrhage SES, socioeconomic status PDA, patent ductus arteriosus MDI, Mental Developmental Index OR, odds ratio CI, confidence interval
Despite advances in perinatal care over the past 2 decades, extremely low birth weight (ELBW) infants remain at high risk in infancy for neurodevelopmental problems such as cerebral palsy (CP), developmental delay, and sensory deficits.1,2 Furthermore, additional problems such as learning disabilities, dyslexia, and hyperactivity-inattention syndromes may be recognized only at school age.3 Multiple reports have identified perinatal medical and demographic factors that are associated with abnormal neurodevelopment. These include serious abnormalities of the sonographic appearance of the brain, chronic lung disease (CLD), decreasing birth weight, sepsis, chorioamnionitis, necrotizing enterocolitis, use of postnatal steroids, and important demographic characteristics such as gender and socioeconomic status.4 Of these factors, the one most strongly associated with CP and delayed mental development is an abnormal head ultrasound (HUS) as a result of lesions such as a large intraventricular hemorrhage (IVH), periventricular leukomalacia, and ventriculomegaly. Although brain injury can occur in preterm infants in the absence of sonographic abnormalities,5 there has been limited investigation of the prevalence of and risk factors for adverse neurodevelopmental outcome among ELBW infants with a normal HUS.
METHODS
This study was conducted among centers of the National Institute of Child Health and Human Development Neonatal Research Network. Patients were included from 14 different centers when they had a birth weight <1000 g; were born between January 1, 1995, and December 31, 1999; were cared for in a network center; had both an early and a late normal HUS; and survived to hospital discharge. Within the network, a uniform schedule of postnatal acquisition of HUSs is not mandated. Most centers attempt to perform HUSs early in life (usually within the first 5–10 days) and either close to the time of discharge or at 36 weeks' postmenstrual age, in addition to other studies on the basis of clinical need. For the cohort of this report, the mean age (±SD) and range for early and late HUSs were 6 ± 5 (range: 0–28) and 47 ± 25 (range: 5–127) days, respectively. A normal HUS was defined as the absence of abnormal intraventricular or periventricular echodensity or echolucency and a normal size of the ventricular system. The interpretations of the HUSs were based on the reports of radiologists at each network center, not by a central reader. Exclusion criteria were the presence of congenital infections and major malformations.
Data About Risk Factors
Data on each mother and infant were collected as part of an ongoing survey of neonatal morbidity and mortality initiated in 1987. Trained research nurses reviewed the medical records of mother and infant and entered predefined data items into a computer database. Additional data about the mother's educational, marital, and financial status were obtained by interviewing the mother around the time of discharge from the hospital. Neonatal outcome data were assessed at discharge from the hospital, 120 days after birth, or at the time of death, whichever came first.
The goal of this study was to identify factors that are associated with adverse neurodevelopmental outcomes (CP and delayed mental development, as defined below) that potentially could be causally related. A large body of evidence suggests that socioeconomic status (SES) influences mental development6–9 and that the construct of SES involves multiple facets.10 Accordingly, several available markers of SES were used: maternal race,2,6,11 age, marital status,6,11,12 maternal education,2,6,8,11,12 medical insurance,8 and household income.10
Physiologic stability during the neonatal period has been associated with mortality,13,14 duration of hospitalization,13,14 perinatal brain damage,15,16 and developmental outcome.17 Risk factors that are potentially indicative of physiologic stability early in life and in the database included outborn status (birth outside of a level III perinatal center),2,18 birth weight,13 estimated gestational age (obstetric criteria),16,19 plurality (singleton or multiple), gender,2,20 and some of the pulmonary and infection variables described below.
Previous research suggests that severity of neonatal pulmonary illness influences the risk for both neurologic and developmental abnormalities.2,21–23 Pulmonary variables included maternal receipt of a full course of antenatal steroids (2 doses of betamethasone at a 24-hour interval or 4 doses of dexamethasone at 12-hour intervals), use of surfactant, occurrence of a pneumothorax, patent ductus arteriosus (PDA) requiring treatment (either indocin or surgery), use of high-frequency ventilation, number of days on conventional ventilation and supplemental oxygen, supplemental oxygen use at 36 weeks' postconceptional age, and treatment with postnatal steroids for lung injury (not including inhaled steroids).
Recently data suggest a role for infection in the causation of perinatal brain damage.24–26 Risk factors related to infection included the use of maternal antibiotics during the admission resulting in delivery, rupture of membranes for >18 hours, early- and late-onset culture-proven sepsis, and definite necrotizing enterocolitis (modified Bell's Staging criteria of IIA, IIB, IIIA, or IIIB2). Human studies suggest that suboptimal nutrition might be a modifiable risk factor for developmental problems in premature infants.27–30 Data related to nutrition included the age at first feed, days to full enteral feeds, days to regain birth weight, and days of parenteral alimentation.
Outcome Data
After discharge from the hospital, infants were invited to undergo a neurodevelopmental assessment at 18 to 22 months' corrected age. Each network center has an established follow-up program that performs developmental evaluation, neurologic assessment, functional performance, and medical/social interviews. The primary outcomes for this study were CP and mental development. Neurologic examinations were based on the Amiel-Tison assessment31 and were performed by certified physicians who had undergone training to ensure reliability in examination findings across centers. CP was defined as a static central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture.2 CP was divided further into mild, moderate, and severe on the basis of the extent of inability to perform age-appropriate motor functions.2 Mental development was determined using the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II, administered by examiners who were trained to ensure reliability against a gold standard examiner. In the standardization sample, the mean and SD were 100 and 15, respectively.32 Infants with very low MDI scores (<50) were assigned a score of 49 in the database.
Data Analysis
Bivariate associations with the primary outcomes (CP, MDI <70, and either CP or MDI <70) were analyzed using 2 tests for categorical variables or t tests for continuous variables. Variables for which the P value was <.10 were selected for multivariate analyses. Multivariate associations were analyzed with logistic regression models using a time-oriented approach for stepwise selection of variables into a logistic model.33 The time-oriented approach uses sequential variable selection to parallel the sequence of risk factors encountered by ELBW infants. In the initial step, only prenatal variables were included as predictors. Beginning with the first step, predictors that were associated with the outcome of interest at .05 level of significance were included in all subsequent steps of the time-oriented model, irrespective of whether they remained significant in the following steps. In the second step, birth weight, gender, and multiple births were added as predictors. The third, fourth, and fifth steps included, respectively, risk factors that are identifiable in the first week of life (eg, pneumothorax), factors that are identifiable during the first weeks of life (eg, late-onset sepsis), and factors that occur late in the hospital course (eg, duration of ventilation). As in the first step, once a variable was identified as statistically significant, it was retained in all subsequent models. In the final logistic regression model, network center was used as a control variable. Thus, a series of stepwise models were created to reflect the multiple points of the time-oriented process, and a step-wise selection procedure was used for each model to ascertain variables that were independently associated with the outcome. The results of the logistic models were expressed as an odds ratio (OR) and 95% confidence interval (CI). Additional analyses were performed to examine the potential role of confounders for the relationship between pneumothorax and CP. Continuous data were described as the mean ± SD; categorical data were described as proportions.
RESULTS
Description of Cohort
Between January 1, 1995, and December 31, 1999, 6905 infants with birth weight <1000 g were admitted within the first 14 days of life to the 14 network centers, and 2378 (34.4%) died before discharge. Of the survivors, 204 were not eligible because they had an intrauterine infection or a major malformation syndrome, and 1802 had at least 1 abnormal ultrasound. Of the remaining 2521 infants, 772 were excluded because there were no ultrasounds (n = 14), there was 1 normal ultrasound with missing information for the other study (n = 318), the first ultrasound was done after 28 days of age (n = 122), there were 2 normal ultrasounds both listed for the same date (n = 313), or there was other missing information on both ultrasounds (n = 5). Of the 1749 infants who met inclusion criteria for the study, 270 did not have follow-up assessments and 6 infants had missing information at follow-up. Surviving infants without cranial ultrasound abnormality were separated into 3 groups relative to the inclusion criteria of this study, and their characteristics are listed in Table 1.
The 1473 infants who met inclusion criteria and underwent neurodevelopmental testing in the network centers compose the study population for this report. Infant characteristics and neonatal morbidities of this cohort were similar to the 270 infants without follow-up assessments except for a higher prevalence of PDA that required treatment. However, the 772 infants who did not have known HUS abnormality and were excluded because of missing information/incorrect timing of HUS were of greater birth weight, higher gestational age, and lower prevalence of neonatal morbidities compared with the 1473 infants of this report. Details of the prevalence of several maternal attributes and neonatal complications and treatments for the 1473 infants are listed in Tables 1 and 2. A complete course of antenatal steroids was administered to 57% of the mothers in the cohort. Rupture of membranes for >18 hours occurred in 26%, and antibiotics were administered to 67% of all mothers before delivery. Study infants had a mean birth weight of 792 ± 134 g and a mean gestational age of 26 ± 2 weeks by obstetric estimate. Multiple births occurred in 22% of the cohort, and outborn infants who were transported to a Neonatal Network center constituted only 7%. The duration of conventional ventilation was 22 ± 21 days, and the length of supplemental oxygen use was 56 ± 36 days. Early-onset sepsis was uncommon (1.1%), but culture-proven late-onset sepsis was documented in 37%. Nutritional characteristics included 20 ± 14 days to achieve full enteral feeds, 30 ± 18 days of parenteral alimentation, and 14 ± 8 days to regain birth weight.
Prevalence of Adverse Neurodevelopmental Outcomes
For the neurologic examination, 1438 of 1473 infants were examined and classified with respect to CP. For the MDI, 1358 of 1473 infants were tested successfully. Of the 115 infants without an MDI score, 55 had missing data (50 for whether they were tested successfully and 5 for missing MDI scores) and 60 could not be tested (nonneurological reasons, eg, illness). CP was diagnosed in 9.4% of the infants, and an MDI of <70 occurred in 25.3%. Either CP or MDI <70 was found in 29.2% of the 1473 infants. The severity for the 139 infants with CP was mild in 86 (61.9%), moderate in 33 (23.7%), and severe in 20 (14.4%). Maternal demographic characteristics were not related to CP but were associated with an MDI <70 on bivariate analysis (Table 2). The relationships between infant characteristics and selected neonatal interventions/morbidities with infant outcome are listed in Tables 3 and 4. Antenatal steroids were not associated with either outcome or a combination of both outcomes. Among children with normal HUSs, significant multivariate associations were found between CP and male gender, multiple births, decreasing birth weight, pneumothorax, and duration of ventilation (Table 5). Late-onset culture-proven sepsis was associated with CP at an earlier step of the analysis, but this association was no longer significant after days of ventilation was added to the model. With the exception of pneumothorax, variables that were associated with CP were also associated with an increased odds of an MDI <70 (Table 5). Infants who were born to mothers with fewer years of education or with either Medicaid or no health insurance also were more likely to have an MDI <70. Factors that were not associated with an MDI <70 in the final model included the occurrence of a pneumothorax or a PDA, duration of parenteral nutrition, and maternal race (black/Hispanic/other). Logistic regression models to detect interactions between maternal demographic variables (maternal race, education, and health insurance) and neonatal risk factors that were independently associated with a low MDI in the final model failed to reveal any significant interactions.
Additional analyses were performed to assess the independent association of CP with pneumothorax by examining the degree to which the association was confounded by other risk factors. Pneumothorax was significantly associated with surfactant use, high-frequency ventilation, oxygen use at 36 weeks' postconceptional age, postnatal steroids, PDA, late-onset culture-positive sepsis, birth weight, duration of conventional ventilation, age at first enteral feed, and duration of parenteral nutrition. Logistic models that contained pneumothorax as well as each of the potential confounders just listed and the first-order interaction term were developed. None of the interaction terms was significant in any model. Another model that contained pneumothorax and all risk factors was developed. Pneumothorax was independently associated with CP in this model including the other risk factors (P < .05).
DISCUSSION
This report presents the neurodevelopmental outcome of ELBW infants who were at 18 to 22 months of age and had no abnormality recorded on an early and late HUS. This cohort of infants represents a group of ELBW survivors who have not been studied as extensively as infants with major morbidities of the central nervous system. Although these infants had normal cranial ultrasound findings, the risk for CP and delayed mental development was high. These outcomes were associated with 2 neonatal complications that are potentially modifiable: pneumothorax and increasing time on mechanical ventilation.
Multiple investigations have been performed to examine the outcome of ELBW infants as survival has improved.34–38 A common finding of virtually all outcome studies of ELBW infants is the prominent association of abnormalities of the HUS and poor neurodevelopmental outcome.39–41 For preterm infants (<33 weeks) who were born between 1979 and 1983, the probability for major neurodevelopmental disorders at 1 year of age increased with worsening severity of sonographic appearance in the first week of life (ie, periventricular/small IVH to large IVH to parenchymal echodensities).42 Similarly, in a geographically representative sample of 1105 low birth weight (<2 kg) infants who were born between 1984 and 1987, risk factors for disabling CP included sonographic abnormalities of parenchymal echodensities, echolucencies, ventricular enlargement, and IVH.43 Parenchymal lesions and ventricular enlargement were independently related to lower intelligence at 6 years of age in the last cohort.44 Comparable conclusions were derived from 5-year follow-up of infants who were <34 weeks' gestation45 and a province-based follow-up at 2 to 3 years of age for infants with a birth weight between 500 and 1249 g.46
On the basis of these reports, the prevailing conclusion is that sonographic abnormalities of parenchymal echodensities and echolucencies and/or ventricular enlargement are powerful predictors of CP and cognitive deficits.42–44,47,48 Conversely, the presence of a normal HUS is regarded as a good predictor of normal development.49 For example, in 184 infants with either a normal HUS or a germinal matrix hemorrhage in the first week of life, 4% had major and 10% had minor neurodevelopmental impairments.42 Similar rates of impairment were reported for infants with a normal HUS at discharge. Aziz et al46 reported disability rates of 8.9% for children at 2 to 3 years of age who had a normal HUS or only a germinal matrix hemorrhage.
The frequency of CP reported here, 9.4%, is close to the upper bound of the 95% CI of 1% to 10% reported by Levene et al49 as the risk for major disability in premature infants who have a normal HUS and receive intensive care. However, the percentage of infants with persistent motor impairment may be lower than 9.4%, because infants who are identified with mild CP at 1 year are often free of motor handicaps at 7 years of age.50 It is unclear whether this applies to mild CP diagnosed at 18 to 22 months. In the current study, mental development was delayed in 25% of the infants, and nearly 30% of infants in this cohort had CP and/or an MDI <70. These prevalences are not surprising given the observation that the predicted risk for major developmental impairment among ELBW infants with neonatal CLD after controlling for HUS abnormalities is 42%.23
There are limitations to our study. The database has information on only 2 sonograms, one performed early and the other acquired late in the hospital course. Although data were recorded for the most abnormal HUS, it is possible that transient abnormalities could occur and resolve in between or after the time of the 2 scans. The absence of ventriculomegaly suggests that large parenchymal interval lesions did not occur. The lack of a central reader for sonographic interpretation and the difficulty in judging subtle abnormalities of HUS such as periventricular echogenicity is a consideration. Studies of interobserver reliability for sonographic diagnoses of IVH and ventriculomegaly demonstrates good interobserver agreement,51 but the echogenicity of the periventricular area in ELBW infants may lead to both over- and underinterpretation of HUS. The absence of detailed information concerning infection limits insight between infection/inflammation and perinatal brain injury.24–26,52
There are 2 potential sources of selection bias. Infants who met inclusion criteria but did not return for follow-up had maternal and neonatal attributes similar to infants who came for follow-up, and bias from this source was probably small. However, infants who were excluded because they had missing ultrasound data were of higher birth weight, were more mature, and had a lower prevalence of multiple neonatal morbidities (Table 1). Neurodevelopmental evaluation of the excluded cohort indicates that 15.5% had an MDI <70, and 6.7% had CP. These data need to be viewed cautiously because 26% and 20% of the excluded cohort had missing data for MDI and CP, respectively. Exclusion of these infants may modestly overestimate the prevalence of impairment among ELBW infants with a normal HUS on the basis of associations in this report.
The present study supports a reexamination of the inference that a normal neonatal HUS is predictive of normal neurodevelopment among ELBW infants. Recent data suggest that HUSs do not detect the full scope of parenchymal brain injury, and abnormalities of echodensities and echolucencies may represent only the "tip of the iceberg."53 Holling et al53 noted that in a majority of infants with CP and unilateral white matter echolucencies, the neurologic deficit is bilateral. Pierrat et al47 reported that in 54% of infants with less severe periventricular leukomalacia, distribution of cysts was unilateral despite preceding bilateral echodensities and subsequent bilateral abnormal signal intensity on MRI. O'Shea noted that a major HUS abnormality was present only in 32% of infants with diplegia, 52% with quadriplegia, and 70% with hemiplegia.54 Similarly, HUS fails to detect all abnormalities of the white matter when compared with neuropathology.55 Finally, MRI in preterm infants suggests a high incidence of cerebral white matter abnormalities without corresponding cystic changes.56
Associations between adverse outcome and male gender, multiple births, and decreasing birth weight have been noted in previous studies, but the biological basis is not clear.2,39,40,57 Days of ventilation, a proxy for CLD, has been associated with an increased risk for CP at 20 months58 and lower IQs at 8 years of age.59 These reports lacked routine use of HUS. Studies that account for gestational age, HUS abnormalities, and social risk factors confirm associations between CLD and worse motor and/or mental developmental outcomes.22,60,61 Although pneumothorax occurred in only 5% of the cohort, 27% of infants with a pneumothorax developed CP, compared with 9% of those without pneumothorax. Pneumothorax might be causally related to brain injury (eg, alterations in hemodynamics and O2 delivery/uptake) or might be a marker of more severe lung disease. Use of postnatal steroids for ventilator dependence in this cohort was associated with CP and MDI <70 on bivariate analysis but was not independently associated with these outcomes in multivariate models. This may reflect that duration of ventilation is highly correlated with postnatal steroid use and the contributions of the 2 variables could not be separated in the multivariate models. Markers for social risk such as maternal education and health insurance were independently associated with poor mental development (Table 5), consistent with previous literature.2,40,45,62–64
The time-oriented approach suggests other potential links with the outcomes of this study. Late-onset sepsis was associated with CP at an earlier step of the analysis but was not significant once duration of ventilation was added to the model. This suggests either that late-onset sepsis is causally related to CP via longer durations of ventilation or that duration of ventilation is a confounder of the relationship between sepsis and CP. The relationship between days of parenteral nutrition and an MDI <70 could be viewed similarly, because the duration of ventilation is the only significant nondemographic variable entered into the model after parenteral nutrition.
Previous reports support the concept that there is an overall favorable prognosis for early childhood neurodevelopment among preterm infants with a normal HUS. The results of the present cohort indicate that the outcome maybe less optimal for ELBW infants. This could reflect multiple non–central nervous system morbidities that complicate the hospitalization of extremely preterm infants. Besides confirming the well-known influence of socioeconomic characteristics on neurodevelopmental outcome, this study suggests that strategies to reduce pneumothorax and the number of days of mechanical ventilation may be of benefit for improving early childhood neurodevelopment.
ACKNOWLEDGMENTS
Other Neonatal Research Network Participants and Centers involved in this study were as follows: University of Cincinnati: Alan Jobe, MD, PhD (Chairman); Case Western Reserve University: Avroy Fanaroff, MD (principal investigator), Nancy Newman, RN, Dee Wilson, MD (follow-up investigator), Bonnie Sinner, RN; University of Texas Southwestern Medical Center: Abbot R. Laptook, MD (principal investigator), Susie Madison, RN, Sue Broyles, MD (follow-up investigator), Jackie Hickman, RN; Wayne State University: Seetha Shankaran, MD (principal investigator), Gerry Muran, RN, Yvette Johnson, MD (follow-up investigator), Debbie Kennedy, RN; University of Tennessee: Sheldon Korones, MD (principal investigator), Tina Hudson, RN, Henrietta Bada, MD (follow-up investigator), Marilyn Williams, RN; University of Miami: Charles Bauer, MD (principal investigator), Amy Hall, RN, Charles Bauer, MD (follow-up investigator), Wendy Griffin, RN; Emory University: Barbara Stoll, MD (principal investigator), Ellen Hale, RN, Barbara Stoll, MD (follow-up investigator), Ellen Hale, RN; University of New Mexico: Lu-Ann Papile, MD (principal investigator), Conra Backstrom, RN, Lu-Ann Papile, MD (follow-up investigator), Ginny Laadt, RN; University of Cincinnati: Edward Donovan, MD (principal investigator), Marcia Mersmann, RN, Jean Steichen, MD (follow-up investigator), Tari Gratton, RN; Indiana University: James Lemons, MD (principal investigator), DeeDee Appel, RN, Anna Dusick, MD (follow-up investigator), Julie Ahlrichs, RN; Yale University: Richard Ehrenkranz, MD (principal investigator), Pat Gettner, RN, Linda Mayes, MD (follow-up investigator), Elaine Sherwonit, RN; Brown University: William Oh, MD (principal investigator), Angelita Hensman, RN, Betty Vohr, MD (follow-up investigator), Cindy Mejia, RN; Stanford University: David Stevenson, MD (principal investigator), Bethany Ball, RN, Susan Hintz, MD (follow-up investigator), Bethany Ball, RN; University of Alabama: Waldemar Carlo, MD (principal investigator), Monica Collins, RN, Kathleen Nelson, MD (follow-up investigator), Susan Johnson, RN; University of Texas at Houston: Jon Tyson, MD (principal investigator), Georgia McDavid, RN, Brenda Morris, MD (follow-up investigator), Kelly Huddleston, RN; Research Triangle Institute: W. Kenneth Poole, PhD (principal investigator), Betty Hasting; National Institute of Child Health and Human Development: Linda L. Wright, MD (principal investigator), Elizabeth M. McClure, MEd.
We thank Karen Kirby and Brenda Vecchio for excellent secretarial support in handling this manuscript.
FOOTNOTES
Accepted Jul 28, 2004.
No conflict of interest declared.
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Doyle LW. Outcome at 5 years of age of children 23 to 27 weeks' gestation: refining the prognosis. Pediatrics. 2001;108 :134 –141
Hack M, Wilson-Costello D, Friedman H, et al. Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992–1995. Arch Pediatr Adolesc Med. 2000;154 :725 –731
Piecuch RE, Leonard CH, Cooper BA, Sehring SA. Outcome of extremely low birth weight infants (500 to 999 grams) over a 12-year period. Pediatrics. 1997;100 :633 –639
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Pinto-Martin JA, Riolo S, Cnaan A, et al. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics. 1995;95 :249 –254
Whitaker AH, Feldman JF, Van Rossem R, et al. Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age. Pediatrics. 1996;98 :719 –729
Fawer CL, Besnier S, Forcada M, Buclin T, Calame A. Influence of perinatal, developmental and environmental factors on cognitive abilities of preterm children without major impairments at 5 years. Early Hum Dev. 1995;43 :151 –164
Aziz K, Vickar DB, Sauve RS, et al. Province-based study of neurologic disability of children weighing 500 through 1249 grams at birth in relation to neonatal cerebral ultrasound findings. Pediatrics. 1995;95 :837 –844
Pierrat V, Duquennoy C, van Haastert IC, et al. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed. 2001;84 :F151 –F156
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Holling EE, Leviton A. Characteristics of cranial ultrasound white-matter echolucencies that predict disability: a review. Dev Med Child Neurol. 1999;41 :136 –139
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Wake Forest University School of Medicine, Winston-Salem, North Carolina
Wayne State School of Medicine, Detroit, Michigan
Research Triangle Institute, Washington, DC
ABSTRACT
Objective. Severe abnormalities of the head ultrasound (HUS) are important predictors of cerebral palsy (CP) and mental retardation, and a normal HUS usually ensures the absence of major impairments. With the increasing survival of extremely low birth weight (ELBW) infants (birth weight <1000 g), the prognostic significance of a normal HUS may differ. This study examined the prevalence of and risk factors for CP and impaired mental development among ELBW infants with a normal HUS.
Methods. Study infants were ELBW infants who were cared for in Neonatal Research Network centers in the years 1995–1999, had a normal early and late HUS, survived to discharge, and returned for follow-up assessments at 18 to 22 months' corrected age. The outcomes of interest were a score <70 on the Bayley Scales of Infant Development-II Mental Developmental Index (MDI) and CP. Risk factors included maternal demographics; infant characteristics; and interventions or morbidities related to the lung, infection, and nutrition. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A time-oriented approach was used to select variables for inclusion in logistic models.
Results. Of 1749 infants with a normal early and late HUS (performed at a mean age of 6 and 47 days, respectively), 1473 (84%) returned for follow-up assessment. Infants had a birth weight of 792 ± 134 g (mean ± SD) and gestational age of 26 ± 2 weeks. Rates of CP and MDI <70 were 9.4% and 25.3%, respectively, and 29.2% of infants had either CP or MDI <70. In multivariate analyses, factors associated with CP were male gender (OR: 1.8; 95% CI: 1.2–2.6), multiple birth, (OR: 1.6; 95% CI: 1.1–2.5), decreasing birth weight (OR: 1.3 for each 100-g decrease; 95% CI: 1.1–1.5), pneumothorax (OR: 2.3; 95% CI: 1.2–4.4), and days of conventional ventilation (OR: 1.2 for each additional 10 days; 95% CI: 1.1–1.3). With the exception of pneumothorax, these same factors were associated with MDI <70, in addition to less maternal education (OR: 1.4; 95% CI: 1.0–1.9) and Medicaid or lack of coverage for maternal insurance (OR: 1.7; 95% CI: 1.2–2.4).
Conclusions. Nearly 30% of ELBW infants with a normal HUS had either CP or a low MDI. Risk factors that are associated with this high rate of adverse outcomes include pneumothorax, prolonged exposure to mechanical ventilation, and educational and economic disadvantage. Improvements in pulmonary care to reduce duration of ventilation and avoid air leaks might improve neurodevelopmental outcome for ELBW infants.
Key Words: brain imaging extremely preterm infants intraventricular hemorrhage neurobehavioral development
Abbreviations: ELBW, extremely low birth weight CP, cerebral palsy CLD, chronic lung disease HUS, head ultrasound IVH, intraventricular hemorrhage SES, socioeconomic status PDA, patent ductus arteriosus MDI, Mental Developmental Index OR, odds ratio CI, confidence interval
Despite advances in perinatal care over the past 2 decades, extremely low birth weight (ELBW) infants remain at high risk in infancy for neurodevelopmental problems such as cerebral palsy (CP), developmental delay, and sensory deficits.1,2 Furthermore, additional problems such as learning disabilities, dyslexia, and hyperactivity-inattention syndromes may be recognized only at school age.3 Multiple reports have identified perinatal medical and demographic factors that are associated with abnormal neurodevelopment. These include serious abnormalities of the sonographic appearance of the brain, chronic lung disease (CLD), decreasing birth weight, sepsis, chorioamnionitis, necrotizing enterocolitis, use of postnatal steroids, and important demographic characteristics such as gender and socioeconomic status.4 Of these factors, the one most strongly associated with CP and delayed mental development is an abnormal head ultrasound (HUS) as a result of lesions such as a large intraventricular hemorrhage (IVH), periventricular leukomalacia, and ventriculomegaly. Although brain injury can occur in preterm infants in the absence of sonographic abnormalities,5 there has been limited investigation of the prevalence of and risk factors for adverse neurodevelopmental outcome among ELBW infants with a normal HUS.
METHODS
This study was conducted among centers of the National Institute of Child Health and Human Development Neonatal Research Network. Patients were included from 14 different centers when they had a birth weight <1000 g; were born between January 1, 1995, and December 31, 1999; were cared for in a network center; had both an early and a late normal HUS; and survived to hospital discharge. Within the network, a uniform schedule of postnatal acquisition of HUSs is not mandated. Most centers attempt to perform HUSs early in life (usually within the first 5–10 days) and either close to the time of discharge or at 36 weeks' postmenstrual age, in addition to other studies on the basis of clinical need. For the cohort of this report, the mean age (±SD) and range for early and late HUSs were 6 ± 5 (range: 0–28) and 47 ± 25 (range: 5–127) days, respectively. A normal HUS was defined as the absence of abnormal intraventricular or periventricular echodensity or echolucency and a normal size of the ventricular system. The interpretations of the HUSs were based on the reports of radiologists at each network center, not by a central reader. Exclusion criteria were the presence of congenital infections and major malformations.
Data About Risk Factors
Data on each mother and infant were collected as part of an ongoing survey of neonatal morbidity and mortality initiated in 1987. Trained research nurses reviewed the medical records of mother and infant and entered predefined data items into a computer database. Additional data about the mother's educational, marital, and financial status were obtained by interviewing the mother around the time of discharge from the hospital. Neonatal outcome data were assessed at discharge from the hospital, 120 days after birth, or at the time of death, whichever came first.
The goal of this study was to identify factors that are associated with adverse neurodevelopmental outcomes (CP and delayed mental development, as defined below) that potentially could be causally related. A large body of evidence suggests that socioeconomic status (SES) influences mental development6–9 and that the construct of SES involves multiple facets.10 Accordingly, several available markers of SES were used: maternal race,2,6,11 age, marital status,6,11,12 maternal education,2,6,8,11,12 medical insurance,8 and household income.10
Physiologic stability during the neonatal period has been associated with mortality,13,14 duration of hospitalization,13,14 perinatal brain damage,15,16 and developmental outcome.17 Risk factors that are potentially indicative of physiologic stability early in life and in the database included outborn status (birth outside of a level III perinatal center),2,18 birth weight,13 estimated gestational age (obstetric criteria),16,19 plurality (singleton or multiple), gender,2,20 and some of the pulmonary and infection variables described below.
Previous research suggests that severity of neonatal pulmonary illness influences the risk for both neurologic and developmental abnormalities.2,21–23 Pulmonary variables included maternal receipt of a full course of antenatal steroids (2 doses of betamethasone at a 24-hour interval or 4 doses of dexamethasone at 12-hour intervals), use of surfactant, occurrence of a pneumothorax, patent ductus arteriosus (PDA) requiring treatment (either indocin or surgery), use of high-frequency ventilation, number of days on conventional ventilation and supplemental oxygen, supplemental oxygen use at 36 weeks' postconceptional age, and treatment with postnatal steroids for lung injury (not including inhaled steroids).
Recently data suggest a role for infection in the causation of perinatal brain damage.24–26 Risk factors related to infection included the use of maternal antibiotics during the admission resulting in delivery, rupture of membranes for >18 hours, early- and late-onset culture-proven sepsis, and definite necrotizing enterocolitis (modified Bell's Staging criteria of IIA, IIB, IIIA, or IIIB2). Human studies suggest that suboptimal nutrition might be a modifiable risk factor for developmental problems in premature infants.27–30 Data related to nutrition included the age at first feed, days to full enteral feeds, days to regain birth weight, and days of parenteral alimentation.
Outcome Data
After discharge from the hospital, infants were invited to undergo a neurodevelopmental assessment at 18 to 22 months' corrected age. Each network center has an established follow-up program that performs developmental evaluation, neurologic assessment, functional performance, and medical/social interviews. The primary outcomes for this study were CP and mental development. Neurologic examinations were based on the Amiel-Tison assessment31 and were performed by certified physicians who had undergone training to ensure reliability in examination findings across centers. CP was defined as a static central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture.2 CP was divided further into mild, moderate, and severe on the basis of the extent of inability to perform age-appropriate motor functions.2 Mental development was determined using the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II, administered by examiners who were trained to ensure reliability against a gold standard examiner. In the standardization sample, the mean and SD were 100 and 15, respectively.32 Infants with very low MDI scores (<50) were assigned a score of 49 in the database.
Data Analysis
Bivariate associations with the primary outcomes (CP, MDI <70, and either CP or MDI <70) were analyzed using 2 tests for categorical variables or t tests for continuous variables. Variables for which the P value was <.10 were selected for multivariate analyses. Multivariate associations were analyzed with logistic regression models using a time-oriented approach for stepwise selection of variables into a logistic model.33 The time-oriented approach uses sequential variable selection to parallel the sequence of risk factors encountered by ELBW infants. In the initial step, only prenatal variables were included as predictors. Beginning with the first step, predictors that were associated with the outcome of interest at .05 level of significance were included in all subsequent steps of the time-oriented model, irrespective of whether they remained significant in the following steps. In the second step, birth weight, gender, and multiple births were added as predictors. The third, fourth, and fifth steps included, respectively, risk factors that are identifiable in the first week of life (eg, pneumothorax), factors that are identifiable during the first weeks of life (eg, late-onset sepsis), and factors that occur late in the hospital course (eg, duration of ventilation). As in the first step, once a variable was identified as statistically significant, it was retained in all subsequent models. In the final logistic regression model, network center was used as a control variable. Thus, a series of stepwise models were created to reflect the multiple points of the time-oriented process, and a step-wise selection procedure was used for each model to ascertain variables that were independently associated with the outcome. The results of the logistic models were expressed as an odds ratio (OR) and 95% confidence interval (CI). Additional analyses were performed to examine the potential role of confounders for the relationship between pneumothorax and CP. Continuous data were described as the mean ± SD; categorical data were described as proportions.
RESULTS
Description of Cohort
Between January 1, 1995, and December 31, 1999, 6905 infants with birth weight <1000 g were admitted within the first 14 days of life to the 14 network centers, and 2378 (34.4%) died before discharge. Of the survivors, 204 were not eligible because they had an intrauterine infection or a major malformation syndrome, and 1802 had at least 1 abnormal ultrasound. Of the remaining 2521 infants, 772 were excluded because there were no ultrasounds (n = 14), there was 1 normal ultrasound with missing information for the other study (n = 318), the first ultrasound was done after 28 days of age (n = 122), there were 2 normal ultrasounds both listed for the same date (n = 313), or there was other missing information on both ultrasounds (n = 5). Of the 1749 infants who met inclusion criteria for the study, 270 did not have follow-up assessments and 6 infants had missing information at follow-up. Surviving infants without cranial ultrasound abnormality were separated into 3 groups relative to the inclusion criteria of this study, and their characteristics are listed in Table 1.
The 1473 infants who met inclusion criteria and underwent neurodevelopmental testing in the network centers compose the study population for this report. Infant characteristics and neonatal morbidities of this cohort were similar to the 270 infants without follow-up assessments except for a higher prevalence of PDA that required treatment. However, the 772 infants who did not have known HUS abnormality and were excluded because of missing information/incorrect timing of HUS were of greater birth weight, higher gestational age, and lower prevalence of neonatal morbidities compared with the 1473 infants of this report. Details of the prevalence of several maternal attributes and neonatal complications and treatments for the 1473 infants are listed in Tables 1 and 2. A complete course of antenatal steroids was administered to 57% of the mothers in the cohort. Rupture of membranes for >18 hours occurred in 26%, and antibiotics were administered to 67% of all mothers before delivery. Study infants had a mean birth weight of 792 ± 134 g and a mean gestational age of 26 ± 2 weeks by obstetric estimate. Multiple births occurred in 22% of the cohort, and outborn infants who were transported to a Neonatal Network center constituted only 7%. The duration of conventional ventilation was 22 ± 21 days, and the length of supplemental oxygen use was 56 ± 36 days. Early-onset sepsis was uncommon (1.1%), but culture-proven late-onset sepsis was documented in 37%. Nutritional characteristics included 20 ± 14 days to achieve full enteral feeds, 30 ± 18 days of parenteral alimentation, and 14 ± 8 days to regain birth weight.
Prevalence of Adverse Neurodevelopmental Outcomes
For the neurologic examination, 1438 of 1473 infants were examined and classified with respect to CP. For the MDI, 1358 of 1473 infants were tested successfully. Of the 115 infants without an MDI score, 55 had missing data (50 for whether they were tested successfully and 5 for missing MDI scores) and 60 could not be tested (nonneurological reasons, eg, illness). CP was diagnosed in 9.4% of the infants, and an MDI of <70 occurred in 25.3%. Either CP or MDI <70 was found in 29.2% of the 1473 infants. The severity for the 139 infants with CP was mild in 86 (61.9%), moderate in 33 (23.7%), and severe in 20 (14.4%). Maternal demographic characteristics were not related to CP but were associated with an MDI <70 on bivariate analysis (Table 2). The relationships between infant characteristics and selected neonatal interventions/morbidities with infant outcome are listed in Tables 3 and 4. Antenatal steroids were not associated with either outcome or a combination of both outcomes. Among children with normal HUSs, significant multivariate associations were found between CP and male gender, multiple births, decreasing birth weight, pneumothorax, and duration of ventilation (Table 5). Late-onset culture-proven sepsis was associated with CP at an earlier step of the analysis, but this association was no longer significant after days of ventilation was added to the model. With the exception of pneumothorax, variables that were associated with CP were also associated with an increased odds of an MDI <70 (Table 5). Infants who were born to mothers with fewer years of education or with either Medicaid or no health insurance also were more likely to have an MDI <70. Factors that were not associated with an MDI <70 in the final model included the occurrence of a pneumothorax or a PDA, duration of parenteral nutrition, and maternal race (black/Hispanic/other). Logistic regression models to detect interactions between maternal demographic variables (maternal race, education, and health insurance) and neonatal risk factors that were independently associated with a low MDI in the final model failed to reveal any significant interactions.
Additional analyses were performed to assess the independent association of CP with pneumothorax by examining the degree to which the association was confounded by other risk factors. Pneumothorax was significantly associated with surfactant use, high-frequency ventilation, oxygen use at 36 weeks' postconceptional age, postnatal steroids, PDA, late-onset culture-positive sepsis, birth weight, duration of conventional ventilation, age at first enteral feed, and duration of parenteral nutrition. Logistic models that contained pneumothorax as well as each of the potential confounders just listed and the first-order interaction term were developed. None of the interaction terms was significant in any model. Another model that contained pneumothorax and all risk factors was developed. Pneumothorax was independently associated with CP in this model including the other risk factors (P < .05).
DISCUSSION
This report presents the neurodevelopmental outcome of ELBW infants who were at 18 to 22 months of age and had no abnormality recorded on an early and late HUS. This cohort of infants represents a group of ELBW survivors who have not been studied as extensively as infants with major morbidities of the central nervous system. Although these infants had normal cranial ultrasound findings, the risk for CP and delayed mental development was high. These outcomes were associated with 2 neonatal complications that are potentially modifiable: pneumothorax and increasing time on mechanical ventilation.
Multiple investigations have been performed to examine the outcome of ELBW infants as survival has improved.34–38 A common finding of virtually all outcome studies of ELBW infants is the prominent association of abnormalities of the HUS and poor neurodevelopmental outcome.39–41 For preterm infants (<33 weeks) who were born between 1979 and 1983, the probability for major neurodevelopmental disorders at 1 year of age increased with worsening severity of sonographic appearance in the first week of life (ie, periventricular/small IVH to large IVH to parenchymal echodensities).42 Similarly, in a geographically representative sample of 1105 low birth weight (<2 kg) infants who were born between 1984 and 1987, risk factors for disabling CP included sonographic abnormalities of parenchymal echodensities, echolucencies, ventricular enlargement, and IVH.43 Parenchymal lesions and ventricular enlargement were independently related to lower intelligence at 6 years of age in the last cohort.44 Comparable conclusions were derived from 5-year follow-up of infants who were <34 weeks' gestation45 and a province-based follow-up at 2 to 3 years of age for infants with a birth weight between 500 and 1249 g.46
On the basis of these reports, the prevailing conclusion is that sonographic abnormalities of parenchymal echodensities and echolucencies and/or ventricular enlargement are powerful predictors of CP and cognitive deficits.42–44,47,48 Conversely, the presence of a normal HUS is regarded as a good predictor of normal development.49 For example, in 184 infants with either a normal HUS or a germinal matrix hemorrhage in the first week of life, 4% had major and 10% had minor neurodevelopmental impairments.42 Similar rates of impairment were reported for infants with a normal HUS at discharge. Aziz et al46 reported disability rates of 8.9% for children at 2 to 3 years of age who had a normal HUS or only a germinal matrix hemorrhage.
The frequency of CP reported here, 9.4%, is close to the upper bound of the 95% CI of 1% to 10% reported by Levene et al49 as the risk for major disability in premature infants who have a normal HUS and receive intensive care. However, the percentage of infants with persistent motor impairment may be lower than 9.4%, because infants who are identified with mild CP at 1 year are often free of motor handicaps at 7 years of age.50 It is unclear whether this applies to mild CP diagnosed at 18 to 22 months. In the current study, mental development was delayed in 25% of the infants, and nearly 30% of infants in this cohort had CP and/or an MDI <70. These prevalences are not surprising given the observation that the predicted risk for major developmental impairment among ELBW infants with neonatal CLD after controlling for HUS abnormalities is 42%.23
There are limitations to our study. The database has information on only 2 sonograms, one performed early and the other acquired late in the hospital course. Although data were recorded for the most abnormal HUS, it is possible that transient abnormalities could occur and resolve in between or after the time of the 2 scans. The absence of ventriculomegaly suggests that large parenchymal interval lesions did not occur. The lack of a central reader for sonographic interpretation and the difficulty in judging subtle abnormalities of HUS such as periventricular echogenicity is a consideration. Studies of interobserver reliability for sonographic diagnoses of IVH and ventriculomegaly demonstrates good interobserver agreement,51 but the echogenicity of the periventricular area in ELBW infants may lead to both over- and underinterpretation of HUS. The absence of detailed information concerning infection limits insight between infection/inflammation and perinatal brain injury.24–26,52
There are 2 potential sources of selection bias. Infants who met inclusion criteria but did not return for follow-up had maternal and neonatal attributes similar to infants who came for follow-up, and bias from this source was probably small. However, infants who were excluded because they had missing ultrasound data were of higher birth weight, were more mature, and had a lower prevalence of multiple neonatal morbidities (Table 1). Neurodevelopmental evaluation of the excluded cohort indicates that 15.5% had an MDI <70, and 6.7% had CP. These data need to be viewed cautiously because 26% and 20% of the excluded cohort had missing data for MDI and CP, respectively. Exclusion of these infants may modestly overestimate the prevalence of impairment among ELBW infants with a normal HUS on the basis of associations in this report.
The present study supports a reexamination of the inference that a normal neonatal HUS is predictive of normal neurodevelopment among ELBW infants. Recent data suggest that HUSs do not detect the full scope of parenchymal brain injury, and abnormalities of echodensities and echolucencies may represent only the "tip of the iceberg."53 Holling et al53 noted that in a majority of infants with CP and unilateral white matter echolucencies, the neurologic deficit is bilateral. Pierrat et al47 reported that in 54% of infants with less severe periventricular leukomalacia, distribution of cysts was unilateral despite preceding bilateral echodensities and subsequent bilateral abnormal signal intensity on MRI. O'Shea noted that a major HUS abnormality was present only in 32% of infants with diplegia, 52% with quadriplegia, and 70% with hemiplegia.54 Similarly, HUS fails to detect all abnormalities of the white matter when compared with neuropathology.55 Finally, MRI in preterm infants suggests a high incidence of cerebral white matter abnormalities without corresponding cystic changes.56
Associations between adverse outcome and male gender, multiple births, and decreasing birth weight have been noted in previous studies, but the biological basis is not clear.2,39,40,57 Days of ventilation, a proxy for CLD, has been associated with an increased risk for CP at 20 months58 and lower IQs at 8 years of age.59 These reports lacked routine use of HUS. Studies that account for gestational age, HUS abnormalities, and social risk factors confirm associations between CLD and worse motor and/or mental developmental outcomes.22,60,61 Although pneumothorax occurred in only 5% of the cohort, 27% of infants with a pneumothorax developed CP, compared with 9% of those without pneumothorax. Pneumothorax might be causally related to brain injury (eg, alterations in hemodynamics and O2 delivery/uptake) or might be a marker of more severe lung disease. Use of postnatal steroids for ventilator dependence in this cohort was associated with CP and MDI <70 on bivariate analysis but was not independently associated with these outcomes in multivariate models. This may reflect that duration of ventilation is highly correlated with postnatal steroid use and the contributions of the 2 variables could not be separated in the multivariate models. Markers for social risk such as maternal education and health insurance were independently associated with poor mental development (Table 5), consistent with previous literature.2,40,45,62–64
The time-oriented approach suggests other potential links with the outcomes of this study. Late-onset sepsis was associated with CP at an earlier step of the analysis but was not significant once duration of ventilation was added to the model. This suggests either that late-onset sepsis is causally related to CP via longer durations of ventilation or that duration of ventilation is a confounder of the relationship between sepsis and CP. The relationship between days of parenteral nutrition and an MDI <70 could be viewed similarly, because the duration of ventilation is the only significant nondemographic variable entered into the model after parenteral nutrition.
Previous reports support the concept that there is an overall favorable prognosis for early childhood neurodevelopment among preterm infants with a normal HUS. The results of the present cohort indicate that the outcome maybe less optimal for ELBW infants. This could reflect multiple non–central nervous system morbidities that complicate the hospitalization of extremely preterm infants. Besides confirming the well-known influence of socioeconomic characteristics on neurodevelopmental outcome, this study suggests that strategies to reduce pneumothorax and the number of days of mechanical ventilation may be of benefit for improving early childhood neurodevelopment.
ACKNOWLEDGMENTS
Other Neonatal Research Network Participants and Centers involved in this study were as follows: University of Cincinnati: Alan Jobe, MD, PhD (Chairman); Case Western Reserve University: Avroy Fanaroff, MD (principal investigator), Nancy Newman, RN, Dee Wilson, MD (follow-up investigator), Bonnie Sinner, RN; University of Texas Southwestern Medical Center: Abbot R. Laptook, MD (principal investigator), Susie Madison, RN, Sue Broyles, MD (follow-up investigator), Jackie Hickman, RN; Wayne State University: Seetha Shankaran, MD (principal investigator), Gerry Muran, RN, Yvette Johnson, MD (follow-up investigator), Debbie Kennedy, RN; University of Tennessee: Sheldon Korones, MD (principal investigator), Tina Hudson, RN, Henrietta Bada, MD (follow-up investigator), Marilyn Williams, RN; University of Miami: Charles Bauer, MD (principal investigator), Amy Hall, RN, Charles Bauer, MD (follow-up investigator), Wendy Griffin, RN; Emory University: Barbara Stoll, MD (principal investigator), Ellen Hale, RN, Barbara Stoll, MD (follow-up investigator), Ellen Hale, RN; University of New Mexico: Lu-Ann Papile, MD (principal investigator), Conra Backstrom, RN, Lu-Ann Papile, MD (follow-up investigator), Ginny Laadt, RN; University of Cincinnati: Edward Donovan, MD (principal investigator), Marcia Mersmann, RN, Jean Steichen, MD (follow-up investigator), Tari Gratton, RN; Indiana University: James Lemons, MD (principal investigator), DeeDee Appel, RN, Anna Dusick, MD (follow-up investigator), Julie Ahlrichs, RN; Yale University: Richard Ehrenkranz, MD (principal investigator), Pat Gettner, RN, Linda Mayes, MD (follow-up investigator), Elaine Sherwonit, RN; Brown University: William Oh, MD (principal investigator), Angelita Hensman, RN, Betty Vohr, MD (follow-up investigator), Cindy Mejia, RN; Stanford University: David Stevenson, MD (principal investigator), Bethany Ball, RN, Susan Hintz, MD (follow-up investigator), Bethany Ball, RN; University of Alabama: Waldemar Carlo, MD (principal investigator), Monica Collins, RN, Kathleen Nelson, MD (follow-up investigator), Susan Johnson, RN; University of Texas at Houston: Jon Tyson, MD (principal investigator), Georgia McDavid, RN, Brenda Morris, MD (follow-up investigator), Kelly Huddleston, RN; Research Triangle Institute: W. Kenneth Poole, PhD (principal investigator), Betty Hasting; National Institute of Child Health and Human Development: Linda L. Wright, MD (principal investigator), Elizabeth M. McClure, MEd.
We thank Karen Kirby and Brenda Vecchio for excellent secretarial support in handling this manuscript.
FOOTNOTES
Accepted Jul 28, 2004.
No conflict of interest declared.
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